Electrochemical preparation of a parameivir intermediate

Abstract

This invention discloses an electrochemical preparation method for a peramivir intermediate, which is (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester. The method involves, under electrochemical conditions, 2-ethylaloxime first undergoes anodic oxidation to an oxynitrile, which then reacts with (1S,4R)-4-(tert-butoxycarbonyl)amino-2-cyclopentenyl-1-carboxylic acid methyl ester (compound I) in a 1,3-dipolar cycloaddition reaction to generate the peramivir intermediate (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester. The advantages of this invention are mainly reflected in the use of a green electrochemical method, improved stereoselectivity of the reaction, avoidance of stoichiometric oxidants, and reduction of waste emissions.

Description

Technical Field

[0001] This invention relates to an electrochemical method for preparing the peramivir intermediate (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester. Background Technology

[0002] Peramivir is a novel cyclopentane-based antiviral drug developed by BioCryst Laboratories in the United States, based on the structures of the prodrugs oseltamivir and zanamivir. Peramivir is primarily used to treat influenza A and B, and has advantages such as fewer adverse reactions and a lower likelihood of developing drug resistance.

[0003] The chemical name of peramivir is (1S,2S,3R,4R)-3-((S)-1-acetamido-2-ethylbutyl)-4-guanidino-2-hydroxycyclopentyl-1-carboxylic acid, and its structural formula is as follows:

[0004]

[0005] Currently, patents for the synthesis of peramivir include CN200610036326.5, CN200810101818.7, and WO2012 / 145932. The mainstream route uses 2-azabicyclo[2,2,1]hept-5-en-3-one as a starting material, and proceeds through ring-opening, amino protection, 1,3-dipolar cycloaddition, reductive ring-opening, acylation, deprotection, hydrolysis, and substitution reactions to obtain peramivir. Among these, (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester is a key intermediate involved in the current mainstream route for peramivir synthesis. It is usually generated by the reaction of cyclopentene compound I with 2-ethylbutanal oxime compound II, as shown in the following reaction formula:

[0006]

[0007] During the above reaction process, the main product compound III and byproducts compound III-1, compound III-2 and compound III-3 are generated. The structures of the byproducts are shown below.

[0008]

[0009] Most of the reported synthetic methods currently available do not have good control over the generation of byproducts, resulting in low final yields (around 70%). At the same time, the reaction requires a large excess of oxidants, such as sodium hypochlorite (NaOCl) or N-chlorosuccinimide (NCS), which makes the reaction poor in atom economy, generates a large amount of waste, and has complicated post-processing operations. Summary of the Invention

[0010] To overcome the aforementioned problems in the preparation process of the existing peramivir intermediate (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester, the present invention aims to provide a green electrochemical preparation method for the peramivir intermediate.

[0011] The technical solution of the present invention is as follows:

[0012] An electrochemical method for preparing a peramivir intermediate involves, under electrochemical conditions, 2-ethylaloxime is first anolylated to an oxynitrile, and then reacted with (1S,4R)-4-(tert-butoxycarbonyl)amino-2-cyclopentenyl-1-carboxylic acid methyl ester (compound I) in a 1,3-dipolar cycloaddition reaction to generate the peramivir intermediate (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester.

[0013] An electrochemical preparation method for a peramivir intermediate, wherein the peramivir intermediate is (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester, the structural formula of which is shown in compound III, and the preparation method includes the following steps:

[0014] Methyl (1S,4R)-4-(tert-butoxycarbonyl)amino-2-cyclopentenyl-1-carboxylic acid ester (as shown in Compound I), 2-ethylbutanal oxime (as shown in Compound II), and a solvent were mixed, and then an electrolyte was added to form an electrolyte system. An anode and cathode were inserted into the electrolyte system, and the anode and cathode were connected to a power source via wires. The reaction was carried out under specific current and temperature. After the reaction was completed, the reaction solution was extracted 2-4 times with dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and recrystallized to obtain the target compound (as shown in Compound III). The reaction formula is as follows:

[0015]

[0016] Furthermore, the electrolyte is selected from one of sodium chloride, sodium iodide, sodium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetraethylammonium chloride, and tetraethylammonium iodide, preferably sodium iodide or sodium bromide.

[0017] Furthermore, the anode and cathode are selected from one of graphite rods, platinum sheets, stainless steel sheets, and graphite felt, respectively, with the anode preferably being a graphite rod and the cathode preferably being a stainless steel sheet.

[0018] Furthermore, the current is 3mA to 30mA, preferably 10mA to 20mA.

[0019] Furthermore, the solvent used in the reaction is selected from one or more of dichloromethane, ethyl acetate, cyclohexane, acetonitrile, tetrahydrofuran, methyl tert-butyl ether, and water; the volume-to-mass ratio of the solvent to compound I is 1.0 to 10.0:1, preferably 2.0 to 6.0:1, with volume in mL and mass in g.

[0020] Furthermore, the solvent is dichloromethane or acetonitrile.

[0021] Furthermore, the molar ratio of compound I to 2-ethylbutanal oxime is 1:1.0 to 6.0, preferably 1:2.0 to 4.0; the molar ratio of compound I to electrolyte is 1:1.0 to 6.0, preferably 1:2.0 to 4.0.

[0022] Furthermore, the reaction temperature is 20℃~60℃, preferably 20℃~30℃; the reaction time is 4~36 hours, preferably 6~24 hours.

[0023] Furthermore, the solvent used for recrystallization is petroleum ether.

[0024] Compared with the prior art, the beneficial technical effects of the present invention are reflected in:

[0025] 1. This invention employs a green electrochemical synthesis method to achieve the 1,3-dipolar cycloaddition reaction between cyclopentene compound I and aldoxime via electrochemical means, which can simply and efficiently prepare peramivir intermediate compound III.

[0026] 2. Electrochemical methods do not require the addition of additional oxidants, and the electrolytes used can be recycled, reducing production costs and emissions of waste.

[0027] 3. This method can effectively suppress the formation of diastereomers, and the total content of all isomers in the system is less than 11%. Attached Figure Description

[0028] Figure 1The liquid phase spectrum of (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester.

[0029] Figure 2 Liquid phase spectrum after the electrochemical preparation of (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester intermediate.

[0030] Figure 3 Methyl methyl ester of (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid 1 H NMR.

[0031] Figure 4 Methyl methyl ester of (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid 13 C NMR. Detailed Implementation

[0032] In Example 1, 1.0 g (4.14 mmol) of (1S,4R)-4-(tert-butoxycarbonyl)amino-2-cyclopentenyl-1-carboxylic acid methyl ester, 1.19 g (10.35 mmol) of 2-ethylbutanal oxime, and 5 mL of dichloromethane were added to a reaction flask. Then, 1.24 g (8.28 mmol) of sodium iodide was added. A graphite rod (8 mm in diameter) was used as the anode, and a stainless steel rod (15 mm × 15 mm × 0.3 mm) was used as the cathode. The anode and cathode were connected to a power supply through wires, and the current was adjusted to 20 mA. The reaction was carried out at 25 °C for 12 hours, and the reaction was monitored by TLC. After the reaction was complete, the reaction solution was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and recrystallized in petroleum ether to give 1.16 g of a white solid, which was (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester, with a yield of 80.0% and a purity >99.5%. HPLC monitoring showed that the total content of byproducts III-1 and III-3 was 10.93%. Compound III-2 was not detected.

[0033] The main product compound III and byproducts III-1, III-2 and III-3 involved in the reaction are as follows:

[0034]

[0035] Spectral characterization of compound III:

[0036] 1 H NMR (400MHz, CDCl3) δ0.85-0.92(m,6H),1.40(s,9H),1.54-1.73(m,4H),1.97-2.02(m,1H),2.04-2.13(m,1H),2.44-2. 51(m,1H),3.16(d,J=8.8Hz,1H),3.56(d,J=8.0Hz,1H),3.73(s,3H),4.18(s,1H),5.18(d,J=14.4Hz,1H),5.58(s,1H). 13 C NMR (100MHz, CDCl3) δ175.1,161.1,155.0,77.0,63.5,55.6,52.5,52.1,40.5,33.4,28.4,25.7,24.0,12.0,10.8.

[0037] Liquid chromatography-mass spectra of purified (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester obtained in Example 1 of this invention. 1 HNMR spectrum and 13 The C NMR spectra are as follows: Figure 1 , Figure 3 and Figure 4 As shown.

[0038] The liquid phase monitoring results of the unpurified reaction solution after the reaction in Example 1 are as follows: Figure 2 As shown.

[0039] In Example 2, 1.0 g (4.14 mmol) of (1S,4R)-4-(tert-butoxycarbonyl)amino-2-cyclopentenyl-1-carboxylic acid methyl ester, 1.19 g (10.35 mmol) of 2-ethylbutanal oxime, and 5 mL of dichloromethane were added to a reaction flask. Then, 1.24 g (8.28 mmol) of sodium iodide was added. A graphite rod (8 mm in diameter) was used as the anode, and a platinum sheet (15 mm × 15 mm × 0.3 mm) was used as the cathode. The anode and cathode were connected to a power source through wires, and the current was adjusted to 20 mA. The reaction was carried out at 25 °C for 12 hours, and the reaction was monitored by TLC. After the reaction was completed, the reaction solution was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and recrystallized in petroleum ether to give 0.90 g of white solid, which was (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester, with a yield of 62.5% and a purity of >99.5%.

[0040] In Example 3, 1.0 g (4.14 mmol) of (1S,4R)-4-(tert-butoxycarbonyl)amino-2-cyclopentenyl-1-carboxylic acid methyl ester, 1.19 g (10.35 mmol) of 2-ethylbutanal oxime, and 5 mL of dichloromethane were added to a reaction flask. Then, 1.24 g (8.28 mmol) of sodium iodide was added. A graphite rod (8 mm in diameter) was used as the anode and another graphite rod (8 mm in diameter) was used as the cathode. The anode and cathode were connected to a power source via wires. The current was adjusted to 20 mA. The reaction was carried out at 25 °C for 12 hours, and the reaction was monitored by TLC. After the reaction was completed, the reaction solution was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and recrystallized in petroleum ether to give 0.80 g of a white solid, which was (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester, with a yield of 55.5% and a purity of >99.5%.

[0041] In Example 4, 1.0 g (4.14 mmol) of (1S,4R)-4-(tert-butoxycarbonyl)amino-2-cyclopentenyl-1-carboxylic acid methyl ester, 1.19 g (10.35 mmol) of 2-ethylbutanal oxime, and 5 mL of dichloromethane were added to a reaction flask. Then, 1.24 g (8.28 mmol) of sodium iodide was added. A graphite felt (15 mm × 15 mm × 4 mm) was used as the anode and a graphite felt (15 mm × 15 mm × 4 mm) was used as the cathode. The anode and cathode were connected to a power source through wires. The current was adjusted to 20 mA. The reaction was carried out at 25 °C for 12 hours and monitored by TLC. After the reaction was completed, the reaction solution was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and recrystallized in petroleum ether to give 0.62 g of a white solid, which was (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester, with a yield of 42.5% and a purity >99.5%.

[0042] In Example 5, 1.0 g (4.14 mmol) of (1S,4R)-4-(tert-butoxycarbonyl)amino-2-cyclopentenyl-1-carboxylic acid methyl ester, 1.19 g (10.35 mmol) of 2-ethylbutanal oxime, and 5 mL of dichloromethane were added to a reaction flask. Then, 0.48 g (8.28 mmol) of sodium chloride was added. A graphite rod (8 mm in diameter) was used as the anode and a stainless steel (15 × 15 × 0.3 mm) was used as the cathode. The anode and cathode were connected to a power source through wires. The current was adjusted to 20 mA and the reaction was carried out at 25 °C for 12 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and recrystallized in petroleum ether to give 0.97 g of a white solid, which was (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester, with a yield of 62.7% and a purity of >99.5%.

[0043] In Example 6, 1.0 g (4.14 mmol) of (1S,4R)-4-(tert-butoxycarbonyl)amino-2-cyclopentenyl-1-carboxylic acid methyl ester, 1.19 g (10.35 mmol) of 2-ethylbutanal, and 5 mL of dichloromethane were added to a reaction flask. Then, 0.85 g (8.28 mmol) of sodium bromide was added. A graphite rod (8 mm in diameter) was used as the anode and a stainless steel (15 × 15 × 0.3 mm) was used as the cathode. The anode and cathode were connected to a power supply via wires. The current was adjusted to 20 mA, and the reaction was carried out at 25 °C for 12 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and recrystallized in petroleum ether to give 1.04 g of white solid, which was (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester, with a yield of 72.0% and a purity of >99.5%.

[0044] In Example 7, 1.0 g (4.14 mmol) of (1S,4R)-4-(tert-butoxycarbonyl)amino-2-cyclopentenyl-1-carboxylic acid methyl ester, 1.19 g (10.35 mmol) of 2-ethylbutanal, and 5 mL of dichloromethane were added to a reaction flask. Then, 2.1 g (8.28 mmol) of tetraethylammonium iodide was added. A graphite rod (8 mm in diameter) was used as the anode and a stainless steel (15 × 15 × 0.3 mm) was used as the cathode. The anode and cathode were connected to a power supply through wires. The current was adjusted to 20 mA and the reaction was carried out at 25 °C for 12 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and recrystallized in petroleum ether to give 0.30 g of a white solid, which was (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester, with a yield of 21.1% and a purity of >99.5%.

[0045] In Example 8, 1.0 g (4.14 mmol) of (1S,4R)-4-(tert-butoxycarbonyl)amino-2-cyclopentenyl-1-carboxylic acid methyl ester, 1.19 g (10.35 mmol) of 2-ethylbutanal, and 5 mL of dichloromethane were added to a reaction flask. Then, 3.0 g (8.28 mmol) of tetrabutylammonium iodide was added. A graphite rod (8 mm in diameter) was used as the anode and a stainless steel (15 × 15 × 0.3 mm) was used as the cathode. The anode and cathode were connected to a power source through wires. The current was adjusted to 20 mA and the reaction was carried out at 25 °C for 12 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and recrystallized in petroleum ether to give 0.41 g of a white solid, which was (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester, with a yield of 28.5% and a purity of >99.5%.

[0046] In Example 9, 1.0 g (4.14 mmol) of (1S,4R)-4-(tert-butoxycarbonyl)amino-2-cyclopentenyl-1-carboxylic acid methyl ester, 1.19 g (10.35 mmol) of 2-ethylbutanal oxime, and 5 mL of ethyl acetate were added to a reaction flask. Then, 1.24 g (8.28 mmol) of sodium iodide was added. A graphite rod (8 mm in diameter) was used as the anode and a stainless steel (15 × 15 × 0.3 mm) was used as the cathode. The anode and cathode were connected to a power supply through wires, and the current was adjusted to 20 mA. The reaction was carried out at 25 °C for 12 hours, and the reaction was monitored by TLC. After the reaction was completed, the reaction solution was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and recrystallized in petroleum ether to give 0.63 g of a white solid, which was (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester, with a yield of 43.7% and a purity of >99.5%.

[0047] In Example 10, 1.0 g (4.14 mmol) of (1S,4R)-4-(tert-butoxycarbonyl)amino-2-cyclopentenyl-1-carboxylic acid methyl ester, 1.19 g (10.35 mmol) of 2-ethylbutanal oxime, and 5 mL of cyclohexane were added to a reaction flask. Then, 1.24 g (8.28 mmol) of sodium iodide was added. A graphite rod (8 mm in diameter) was used as the anode and a stainless steel (15 × 15 × 0.3 mm) was used as the cathode. The anode and cathode were connected to a power supply through wires. The current was adjusted to 20 mA and the reaction was carried out at 25 °C for 12 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and recrystallized in petroleum ether to give 0.49 g of a white solid, which was (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester, with a yield of 34.1% and a purity of >99.5%.

[0048] In Example 11, 1.0 g (4.14 mmol) of (1S,4R)-4-(tert-butoxycarbonyl)amino-2-cyclopentenyl-1-carboxylic acid methyl ester, 1.19 g (10.35 mmol) of 2-ethylbutanal oxime, and 5 mL of acetonitrile were added to a reaction flask. Then, 1.24 g (8.28 mmol) of sodium iodide was added. A graphite rod (8 mm in diameter) was used as the anode and a stainless steel (15 × 15 × 0.3 mm) was used as the cathode. The anode and cathode were connected to a power supply through wires. The current was adjusted to 20 mA and the reaction was carried out at 25 °C for 12 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and recrystallized in petroleum ether to give 0.95 g of a white solid, which was (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester, with a yield of 65.5% and a purity of >99.5%.

[0049] In Example 12, 1.0 g (4.14 mmol) of (1S,4R)-4-(tert-butoxycarbonyl)amino-2-cyclopentenyl-1-carboxylic acid methyl ester, 1.19 g (10.35 mmol) of 2-ethylbutanal oxime, and 5 mL of tetrahydrofuran were added to a reaction flask. Then, 1.24 g (8.28 mmol) of sodium iodide was added. A graphite rod (8 mm in diameter) was used as the anode and a stainless steel (15 × 15 × 0.3 mm) was used as the cathode. The anode and cathode were connected to a power supply through wires. The current was adjusted to 20 mA and the reaction was carried out at 25 °C for 12 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and recrystallized in petroleum ether to give 0.88 g of a white solid, which was (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester, with a yield of 60.7% and a purity of >99.5%.

[0050] In Example 13, 1.0 g (4.14 mmol) of (1S,4R)-4-(tert-butoxycarbonyl)amino-2-cyclopentenyl-1-carboxylic acid methyl ester, 1.19 g (10.35 mmol) of 2-ethylbutanal oxime, and 5 mL of methyl tert-butyl ether were added to a reaction flask. Then, 1.24 g (8.28 mmol) of sodium iodide was added. A graphite rod (8 mm in diameter) was used as the anode and a stainless steel (15 × 15 × 0.3 mm) was used as the cathode. The anode and cathode were connected to a power supply through wires, and the current was adjusted to 20 mA. The reaction was carried out at 25 °C for 12 hours, and the reaction was monitored by TLC. After the reaction was completed, the reaction solution was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and recrystallized in petroleum ether to give 0.35 g of a white solid, which was (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester, with a yield of 24.3% and a purity of >99.5%.

[0051] In Example 14, 1.0 g (4.14 mmol) of (1S,4R)-4-(tert-butoxycarbonyl)amino-2-cyclopentenyl-1-carboxylic acid methyl ester, 1.19 g (10.35 mmol) of 2-ethylbutanal oxime, and 5 mL of dichloromethane were added to a reaction flask. Then, 1.24 g (8.28 mmol) of sodium iodide was added. A graphite rod (8 mm in diameter) was used as the anode and a stainless steel (15 × 15 × 0.3 mm) was used as the cathode. The anode and cathode were connected to a power source through wires. The current was adjusted to 3 mA. The reaction was carried out at 25 °C for 12 hours and monitored by TLC. After the reaction was completed, the reaction solution was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and recrystallized in petroleum ether to give 0.37 g of a white solid, which was (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester, with a yield of 25.8% and a purity of >99.5%.

[0052] In Example 15, 1.0 g (4.14 mmol) of (1S,4R)-4-(tert-butoxycarbonyl)amino-2-cyclopentenyl-1-carboxylic acid methyl ester, 1.19 g (10.35 mmol) of 2-ethylbutanal oxime, and 5 mL of dichloromethane were added to a reaction flask. Then, 1.24 g (8.28 mmol) of sodium iodide was added. A graphite rod (8 mm in diameter) was used as the anode and a stainless steel (15 × 15 × 0.3 mm) was used as the cathode. The anode and cathode were connected to a power source through wires, and the current was adjusted to 30 mA. The reaction was carried out at 25 °C for 12 hours, and the reaction was monitored by TLC. After the reaction was completed, the reaction solution was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and recrystallized in petroleum ether to give 0.99 g of a white solid, which was (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester, with a yield of 68.2% and a purity of >99.5%.

[0053] In Implementation Case 16, 1.0 g (4.14 mmol) of (1S,4R)-4-(tert-butoxycarbonyl)amino-2-cyclopentenyl-1-carboxylic acid methyl ester, 2.86 g (24.84 mmol) of 2-ethylbutanal oxime, and 5 mL of dichloromethane were added to a reaction flask. Then, 1.24 g (8.28 mmol) of sodium iodide was added. A graphite rod (8 mm in diameter) was used as the anode, and a stainless steel rod (15 mm × 15 mm × 0.3 mm) was used as the cathode. The anode and cathode were connected to a power supply via wires, and the current was adjusted to 20 mA. The reaction was carried out at 25 °C for 12 hours, and the reaction was monitored by TLC. After the reaction was completed, the reaction solution was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and recrystallized in petroleum ether to give 1.15 g of white solid, which was (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester, with a yield of 79.3% and a purity of >99.5%.

[0054] In Implementation Case 17, 1.0 g (4.14 mmol) of (1S,4R)-4-(tert-butoxycarbonyl)amino-2-cyclopentenyl-1-carboxylic acid methyl ester, 1.19 g (10.35 mmol) of 2-ethylbutanal oxime, and 5 mL of dichloromethane were added to a reaction flask. Then, 3.72 g (24.84 mmol) of sodium iodide was added. A graphite rod (8 mm in diameter) was used as the anode, and a stainless steel rod (15 mm × 15 mm × 0.3 mm) was used as the cathode. The anode and cathode were connected to a power supply via wires, and the current was adjusted to 20 mA. The reaction was carried out at 25 °C for 12 hours, and the reaction was monitored by TLC. After the reaction was completed, the reaction solution was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and recrystallized in petroleum ether to give 1.14 g of white solid, which was (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester, with a yield of 78.5% and a purity of >99.5%.

[0055] In Example 18, 1.0 g (4.14 mmol) of (1S,4R)-4-(tert-butoxycarbonyl)amino-2-cyclopentenyl-1-carboxylic acid methyl ester, 1.19 g (10.35 mmol) of 2-ethylbutanal oxime, and 5 mL of dichloromethane were added to a reaction flask. Then, 1.24 g (8.28 mmol) of sodium iodide was added. A graphite rod (8 mm in diameter) was used as the anode and a stainless steel (15 × 15 × 0.3 mm) was used as the cathode. The anode and cathode were connected to a power supply through wires, and the current was adjusted to 30 mA. The reaction was carried out at 60 °C for 12 hours, and the reaction was monitored by TLC. After the reaction was completed, the reaction solution was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and recrystallized in petroleum ether to give 0.59 g of a white solid, which was (3aR,4R,6S,6aS)-4-hydroxy-3-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopentyl[d]isoxazole-6-carboxylic acid methyl ester, with a yield of 41.0% and a purity of >99.5%.

Claims

1. An electrochemical preparation method for a peramivir intermediate, wherein the structural formula of the peramivir intermediate is shown in compound III, characterized in that... Includes the following steps: Methyl (1S,4R)-4-(tert-butoxycarbonyl)amino-2-cyclopentenyl-1-carboxylic acid ester (as shown in Compound I), 2-ethylbutanal oxime (as shown in Compound II), and a solvent were mixed, and then an electrolyte was added to form an electrolyte system. An anode and cathode were inserted into the electrolyte system, and the anode and cathode were connected to a power source via wires. The reaction was carried out under specific current and temperature. After the reaction was completed, the reaction solution was extracted 2-4 times with dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and recrystallized to obtain the target compound (as shown in Compound III). The reaction formula is as follows: ； The electrolyte is selected from sodium iodide or sodium bromide; The anode is a graphite rod, and the cathode is a stainless steel sheet; The current range is 10 mA to 20 mA. The solvent is dichloromethane or acetonitrile.

2. The electrochemical preparation method of a peramivir intermediate as described in claim 1, characterized in that... The volume-to-mass ratio of the solvent to compound I is 1.0 to 10.0:1, with volume in mL and mass in g.

3. The electrochemical preparation method of a peramivir intermediate as described in claim 2, characterized in that... The volume-to-mass ratio of the solvent to compound I is 2.0 to 6.0:1, with volume in mL and mass in g.

4. The electrochemical preparation method of a peramivir intermediate as described in claim 1, characterized in that... The molar ratio of compound I to 2-ethylbutanal oxime is 1:1.0~6.0; the molar ratio of compound I to electrolyte is 1:1.0~6.

0.

5. The electrochemical preparation method of a peramivir intermediate as described in claim 4, characterized in that... The molar ratio of compound I to 2-ethylbutanal oxime is 1:2.0~4.0; the molar ratio of compound I to electrolyte is 1:2.0~4.

0.

6. The electrochemical preparation method of a peramivir intermediate as described in claim 1, characterized in that... The reaction temperature is 20 ℃~60 ℃; the reaction time is 4~36 hours.

7. The electrochemical preparation method of a peramivir intermediate as described in claim 6, characterized in that... The reaction temperature is 20 ℃~30 ℃; the reaction time is 6~24 hours.

8. The electrochemical preparation method of a peramivir intermediate as described in claim 1, characterized in that... The solvent used for recrystallization is petroleum ether.

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